Effects of FSGS factor on arachidonic acid metabolism

FSGS因子对花生四烯酸代谢的影响

• 批准号: 6464306
• 负责人: ELLEN T MCCARTHY
• 金额: $ 7.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6464306
• 关键词: clinical research; eicosanoid metabolism; enzyme activity; glomerulosclerosis; human subject; laboratory rat; pathologic process; phospholipase A2; polymerase chain reaction; prostaglandin endoperoxide synthase; proteins; thromboxanes

DESCRIPTION (provided by candidate): Focal segmental glomerulosclerosis (FSGS) is characterized by heavy proteinuria and progression to end-stage renal disease. The incidence of FSGS has increased markedly over the past 20 years, and is the most common cause of primary nephrotic syndrome in adults in several series. The cyclooxygenase inhibitor indomethacin decreases proteinuria in patients with FSGS, implicating a product of arachidonic acid metabolism as a mediator of proteinuria. A low molecular weight protein in plasma of patients with FSGS (referred to as the FSGS factor) increases albumin permeability of isolated glomeruli. Presence of the FSGS factor is associated with and predictive of recurrence of disease in renal allografts. Work funded by my K08 grant demonstrated that the FSGS factor increases glomerular albumin permeability by stimulating the arachidonic acid cyclooxygenase and thromboxane A-2 synthase pathways. Also, the FSGS factor releases arachidonic acid from isolated glomeruli and stimulates prostaglandin EZ synthesis. In preliminary studies, I have shown increased expression of phospholipase A-2, cyclooxygenase-2 (COX-2) and thromboxane A-2 synthase in kidneys of rats injected with the FSGS factor. The proposed studies will further explore this effect. The Specific Aim is to determine whether the FSGS factor alters in vivo glomerular expression of key enzymes of arachidonic acid metabolism. Rats will be injected with the FSGS factor or an identical fraction of normal plasma. Kidney tissue (kidney slices or isolated glomeruli) will be examined at various time points for mRNA and protein levels of phospholipase A2, COX-1, COX-2 and thromboxane A2 synthase using Western blotting and RT-PCR. Results will be correlated with glomerular albumin permeability and with urinary excretion of protein and eicosanoids. Results of the proposed experiments will provide the groundwork for further studies to explore transcriptional regulation of phospholipase A2, COX-1, COX-2 and thromboxane A2 synthase by the FSGS factor. These studies will provide insight into the pathophysiology of proteinuria in patients with recurrent FSGS and may lead to novel treatment strategies in these patients.

描述（由候选人提供）： 局灶节段性肾小球硬化症（FSGS）的特征是大量蛋白尿 并进展为终末期肾病。FSGS的发病率有所增加 在过去的20年里，这是最常见的主要原因。 成人肾病综合征的几个系列。环氧酶抑制剂 吲哚美辛减少FSGS患者的蛋白尿，涉及一种产品 花生四烯酸代谢作为蛋白尿的介质。 FSGS患者血浆中的一种低分子量蛋白质（称为 FSGS因子）增加分离的肾小球的白蛋白渗透性。存在 FSGS因子与疾病复发相关并可预测疾病复发 移植肾的情况由我的K 08基金资助的工作表明， 因子通过刺激花生四烯酸， 酸性环氧合酶和血栓素A-2合酶途径。此外，FSGS 因子从分离的肾小球释放花生四烯酸并刺激 前列腺素EZ合成。在初步研究中，我发现 磷脂酶A-2、环氧合酶-2（考克斯-2）和血栓素A-2的表达 在注射FSGS因子的大鼠的肾脏中的FSGS合成酶。拟议的研究 我们将进一步探讨这种影响。具体目标是确定 FSGS因子改变花生四烯酸关键酶在体内肾小球的表达 酸代谢 将向大鼠注射FSGS因子或正常水平的相同分数 等离子体将在以下时间检查肾组织（肾切片或分离的肾小球）： 磷脂酶A2，考克斯-1， Western blotting和RT-PCR检测考克斯-2和血栓素A2合酶。结果 将与肾小球白蛋白渗透性和尿 蛋白质和类花生酸的排泄。 所提出的实验结果将为进一步的研究奠定基础。 研究探索磷脂酶A2、考克斯-1、考克斯-2的转录调控 和血栓素A2合酶通过FSGS因子。这些研究将提供 对复发性FSGS患者蛋白尿病理生理学的认识 并可能为这些患者带来新的治疗策略。